Sphingolipid as one of the cell membrane-constituting lipid-soluble components contains two kinds, sphingomyelin and glycolipid. They are converted into ceramides enzymatically via sphingomyelinase and endoglycanase, and then metabolized into sphingosine by a ceramidase. Furthermore, the sphingosine is then converted into sphingosine 1-phosphate (hereinafter referred to as “S1P”) by a sphingosine kinase.
Studies on such intracellular metabolism of sphingolipid have been carried out since 1960's, but until now, S1P has been recognized only as one of the intermediate metabolic products in the sphingolipid metabolism. However, S1P is focused because its physiological activities are being revealed recently.
For example, the followings are known as the activities possessed by S1P.    (1) Cell growth accelerating activity on Swiss 3T3 fibroblast by calcium mobilization (J. Cell. Biol., 114, 155–167 (1991)).    (2) Control of cellular chemotactic activity of a cancer cell line (Proc. Natl. Acad. Sci. USA, 89, 9686–9690 (1992)).    (3) Inhibition of PDGF (platelet-derived growth factor)-dependent cellular mobilization of smooth muscle cells (J. Cell. Biol., 130, 193–206 (1995)).    (4) Function as a second messenger. For example, S1P acts as an intracellular second messenger in a cell growth stimulation by PDGF etc. (Nature, 365, 557–560 (1993)) and it also acts as an intracellular second messenger in the intracellular calcium mobilization via a high affinity IgE receptor of a rat mast cell, RBL-2H3 cell (Nature, 380, 634–636 (1996)).    (5) Inhibition of apoptosis by ceramide etc. (Nature, 381, 800–803 (1996)). Opposite activity is suggested a possibility that it acts as a signal molecule of apoptosis induction of leukocyte (FEBS Lett., 355, 267 (1995)), which may have a different mechanism.    (6) Since S1P has been reported to act as an extracellular moiety via a cell surface receptor, its role as an intercellular messenger is also focused. In addition, with the recent advance in the identification and cloning of S1P receptors, Edg-1 (endothelial cell differentiation gene-1), Edg-3, AGR16/H218 (Edg-5), Edg-6 and Edg-8 have been reported as specific S1P receptors (Science, 279, 1552–1555 (1998), Biochem. J., 330, 605–609 (1998), FEBS Lett., 417, 279–282 (1997), Blood, 95, 2624–2629 (2000), J. Biol. Chem., 275, 14281–14286 (2000)).
The specification of WO 93/19760 (JP-T-8-500816) describes a method for using S1P in the inhibition of active chemotactic property of tumor cells, inhibition of invasion of tumor cells, inhibition of inflammation by the active property of neutrophils, inhibition of metastasis of malignant tumor cells etc.
The specification is provided that a method for inhibiting inflammation. However, it merely describes that since the inflammation steps are dependent on the mobilization of neutrophils, S1P which inhibits the mobilization is expected to be useful in inhibiting the inflammation steps.
The specification of U.S. Pat. No. 5,712,262 describes that S1P suppressed programmed cell death.
While various physiological activities of S1P are being revealed as described above, its activities regarding fibrosis are also studied. For example, as shown in the above item (1), it has been confirmed that S1P accelerates cell growth of Swiss 3T3 fibroblast and acts as an intracellular signal molecule which mobilizes calcium from its intracellular store, and it has been confirmed thereafter that sphingosine derivatives have activities similar to S1P (J. Biol. Chem., 273(36), 23585–23589 (1998)). Thus, it has been reported that S1P and its related substances are concerned in the growth of fibroblast.